tbuckley/cabot-search huggingface dataset:
Abstract 4021: CTS2016, a novel AXL/FLT3 inhibitor for targeting AML/MDS and solid tumors
Authors: Hui Shi, Meng Wang, Jiaxin Huang, Qiugeng Ouyang, Jiannan Guo, Youzhen Wang, Yuan Mi, Haiping Wu
Journal: Cancer Research (2023)

Abstract We identified CTS2016 as a novel, selective, orally bioavailable small molecule inhibitor with single-digit nanomolar enzymatic activity to AXL and FLT3. Overexpression of AXL is associated with metastasis, drug resistance, and poor prognosis of various hematological and solid tumors, which are all broadly modulated with epigenetic regulation. In addition, inhibition of AXL phosphorylation may overcome drug resistance to current FLT3 inhibitors in FLT3-ITD+ Acute Myeloid Leukemia (AML) (Park et al., 2015). We tested CTS2016 as a single agent or in combination with either venetoclax, a Bcl-2 inhibitor, or azacitidine, a hypomethylating agent (HMA) and an epigenetic modulation drug, in a series of in vitro and in vivo studies using various AML models CTS2016 resulted in a potent growth inhibitory effect with strong induction of cell death in a spectrum of AML cell lines carrying FLT3 mutations (FLT3-ITD and/or FLT3-TKD) CTS2016 orally administered once daily, demonstrated potent and dose-dependent antitumor responses in a variety of AML xenograft mouse models. The anti-tumor activity was correlated with the inhibition of receptor tyrosine kinase signaling, as measured by decreased phosphorylation of key downstream signaling targets of FLT3. In a tail vein injection of mouse LLC-Luciferase model, CTS2016 treatment could significantly reduce tumor metastasis. A combination of CTS2016 with venetoclax or azacitidine provides a therapeutic benefit over monotherapy and supports a rationale for testing these combination therapies in patients with relapsed or refractory (R/R) AML and myelodysplastic syndromes (MDS). In addition, CTS2016 significantly reduced the tumor burden of a leukemia model harboring FLT3-ITD-F691L, a drug-resistant mutation of FLT3. Notably, the selectivity of CTS2016 over other kinases (such as c-KIT) mitigates the off-target toxicity effects on normal hematological differentiation which is common in clinics for other FLT3 inhibitors. These data demonstrate that CTS2016 could be a promising therapy for treating patients diagnosed with AML and MDS harboring FLT3 mutations and solid tumors such as NSCLC and TNBC with high-expression of AXL. More proof-of-concept data would come from the ongoing clinical trial. Citation Format: Hui Shi, Meng Wang, Jiaxin Huang, Qiugeng Ouyang, Jiannan Guo, Youzhen Wang, Yuan Mi, Haiping Wu. CTS2016, a novel AXL/FLT3 inhibitor for targeting AML/MDS and solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4021.
Abstract 6212: Inhibition of ATM-dependent checkpoint control and DNA double-strand break repair enhances the efficacy of ATR inhibitors
Authors: Audrey Turchick, Astrid Zimmermann, Li-Ya Chiu, Heike Dahmen, Brian Elenbaas, Frank T. Zenke, Andree Blaukat, Lyubomir T. Vassilev
Journal: Cancer Research (2023)

Abstract Ataxia telangiectasia and Rad3 related (ATR) and ataxia telangiectasia mutated (ATM) protein kinases play key roles in the DNA damage response (DDR) by responding to replication stress and double-strand DNA breaks respectively to pause the cell cycle and promote DNA repair. ATR kinase inhibition in cancer cells disrupts cell cycle control and causes unrepaired DNA lesions and cytotoxicity. Accordingly, several ATR inhibitors (ATRi) are in clinical development as monotherapies and in combination with DNA damaging chemotherapies and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that while treatment of cancer cells with an ATRi inhibits the ATR pathway, it simultaneously activates the ATM signaling pathway as shown by increased levels of p-ATM, p-CHK2, p-KAP1 and p-p53. In p53 wild-type cancer cells, ATR inhibition causes an ATM-mediated G1 cell cycle arrest which diminishes the DNA lesions and cytotoxic effects of ATR inhibition. Combination of an ATRi with a selective ATM inhibitor (ATMi) synergistically potentiated efficacy in cancer cells in vitro and increased efficacy in vivo at doses that did not show overt toxicities. In a panel of patient-derived xenograft (PDX) models of triple-negative breast cancer treated with an ATRi/ATMi combination, substantial improvement in efficacy was observed. Thus, activation of the ATM pathway by an ATRi acts as a compensatory resistance pathway for ATR inhibition. These results suggest a novel and efficacious combination approach for cancer therapy by dual inhibition of these two key DDR kinases. Citation Format: Audrey Turchick, Astrid Zimmermann, Li-Ya Chiu, Heike Dahmen, Brian Elenbaas, Frank T. Zenke, Andree Blaukat, Lyubomir T. Vassilev. Inhibition of ATM-dependent checkpoint control and DNA double-strand break repair enhances the efficacy of ATR inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6212.
Abstract 4043: Stimulation of the mapk and pi3k/akt pathways in pancreatic cancer cells by polyisoprenylated cysteinyl amide inhibitors
Authors: Kweku Ofosu-Asante, Jassy M. Lazarte, Amarendar G. Burra, Nazarius S. Lamango
Journal: Cancer Research (2023)

Abstract Pancreatic cancer is the third deadliest cancer with a 5-year survival rate of less than 10%. Over 90% of reported cases are driven by KRAS mutations. KRAS signals through the MAPK and PI3K pathways. Targeting mutant KRAS has been a decades-long challenge until recently whereby drugs that react with specific mutant proteins have been developed. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) are potential anticancer agents with an alternative design strategy targeting polyisoprenylation-dependent processes of hyperactive mutant or overexpressed G-proteins. The effect of PCAIs on the viability and downstream mediators of KRAS signaling was determined on PANC-1 and MIAPaCa-2 cells. Of the 16 different analogs tested, NSL-YHJ-2-45 and NSL-YHJ-2-27 were the most potent with EC50 values of 3.6 and 3.8 against PANC-1 cells, respectively. For MIAPaCa-2 cells, NSL-YHJ-2-27 was the most potent with an EC50 value of 2.2. Western blotting analysis of PCAIs-treated PANC-1 cells revealed that phosphorylated BRAF, MEK 1/2, ERK 1/2 and p90RSK increased by 64, 129, 152 and 79%, respectively, while phosphorylated CRAF levels decreased by 27%. Moreover, monomeric G-proteins, CDC42, RHOA and RAC 1/2/3 protein levels decreased by 20, 58 and 13%, respectively. NSL-YHJ-2-27 (5 µM) also increased the levels of pAKT (Ser 473) and pAKT (Thr 308) by 72 and 192%, respectively. When MIAPaCa-2 cells were treated with 0-5 µM NSL-YHJ-2-27, MEK 1/2, ERK 1/2 and p90RSK phosphorylation increased by 78, 270 and 260%, respectively. However, at 5 µM NSL-YHJ-2-27, there were no significant changes in protein levels of the monomeric G proteins RAC 1/2/3 and RHOA, but protein levels of CDC42 increased by 132%. NSL-YHJ-2-27 (5 µM) increased the levels of pAKT (Ser 473) and pAKT (Thr 308) of MIAPaCa-2 cells by 97 and 82%, respectively. The results indicate the effect of PCAIs on the phosphorylation of important kinases involved in MAPK and AKT pathways. These effects on these signaling pathways strongly indicate the potential of the PCAIs against RAS-driven cancers. Citation Format: Kweku Ofosu-Asante, Jassy M. Lazarte, Amarendar G. Burra, Nazarius S. Lamango. Stimulation of the mapk and pi3k/akt pathways in pancreatic cancer cells by polyisoprenylated cysteinyl amide inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4043.
Abstract 3075: Enhanced efficacy of ARV-471, a novel PROTAC® estrogen receptor degrader, in combination with targeted agents in estrogen receptor-positive (ER+) breast cancer models
Authors: Jessica Teh, Elizabeth Bortolon, Jennifer Pizzano, Melissa Pannone, Sean Landrette, Richard Gedrich, Ian Taylor
Journal: Cancer Research (2023)

Abstract ARV-471 is a selective, orally bioavailable PROteolysis-TArgeting Chimera (PROTAC®) small molecule that induces wild-type and mutant estrogen receptor (ER) alpha degradation via the ubiquitin-proteasome system. ARV-471 demonstrates superior ER degradation and antitumor activity compared to fulvestrant in endocrine sensitive and resistant xenograft models and has shown significant ER degradation and promising clinical benefit in late-line ER+ breast cancer patients. Dual pathway inhibition combining ER targeting agents with CDK4/6 or PIK3CA/mTOR pathway inhibitors is now a central strategy for treatment of advanced ER+ breast cancer. However, resistance to aromatase inhibitors resulting from ESR1 gene mutations, suboptimal ER degradation and the intramuscular route of administration of fulvestrant underscore a need for superior orally bioavailable endocrine therapy backbones for these combinations. Here, we assessed the effects of ARV-471 in combination with CDK4/6 or PIK3CA/mTOR pathway inhibitors in preclinical models of ER+ breast cancer. In vitro studies revealed evidence of synergistic interactions between ARV-471 and the CDK4/6 inhibitors abemaciclib and ribociclib, the mTOR inhibitor everolimus, or the PIK3CA inhibitors alpelisib and inavolisib in ER+ breast cancer cells. Evidence of synergistic effects between ARV-471 and everolimus was also observed in ER+ breast cancer cells expressing ER Y537S or D538G mutations. ARV-471 in combination with CDK4/6, PIK3CA or mTOR inhibitors led to tumor regressions in MCF7 xenografts when compared to single agents alone. ARV-471 also displayed greater anti-tumor activity in combination with abemaciclib, ribociclib or inavolisib than that observed with fulvestrant in combination with these agents. Taken together, these data suggest the potential utility of ARV-471 as a combination partner for clinically relevant targeted agents for treatment of early and late-stage ER+ disease. Citation Format: Jessica Teh, Elizabeth Bortolon, Jennifer Pizzano, Melissa Pannone, Sean Landrette, Richard Gedrich, Ian Taylor. Enhanced efficacy of ARV-471, a novel PROTAC® estrogen receptor degrader, in combination with targeted agents in estrogen receptor-positive (ER+) breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3075.
Abstract 2705: Low-dose crystalline cytokine macrophage mediated Trojan horse immunotherapy of solid cancers
Authors: Michael H. Jones, Nirk E. Quispe Calla, Callum Talbot-Cooper, Hong Zeng, Jonathan Best, Robert Smith
Journal: Cancer Research (2023)

Abstract Protein therapeutics are often compromised by sub-optimal biodistribution contributing to poor efficacy and adverse events. Drug delivery mechanisms better able to target the disease site and provide localized, sustained drug release have the potential to transform therapeutic standards. PODS crystals (PCs) are natural-mimetic, micron-scale protein co-crystals engineered to incorporate a protein cargo that is sustainably released under the action of resident proteases. PCs are efficiently taken up by phagocytic cells and their cargo protein is subsequently released in a bioactive form. Since blood-circulating phagocytic cells, including monocytes, are actively recruited into the tumor microenvironment, we postulated that monocyte/macrophage-mediated PC delivery could be used as a molecular “Trojan horse” to efficiently deliver therapeutic proteins to target cells. This could improve the pharmacodynamics and pharmacokinetics of protein drug delivery to treat systemic and disseminated diseases. Interleukin-2 (IL-2) is notoriously toxic at the high doses required for therapeutic efficacy. Here, we demonstrate the therapeutic efficacy and tolerability of low doses of PC-IL-2 administered intravenously in a mouse model of melanoma. We further demonstrate the therapeutic benefit of PCs delivering low doses of IL-2, interleukin-15 (IL-15) and interferon-gamma (IFN-γ) in a mouse model of renal cell carcinoma. In all the treated mice, cachexia, a side effect of high-dose cytokine therapy, was notably absent. This study provides proof-of-concept for the utility of intravenously administered PCs to provide a generalised and widely applicable mechanism to effectively deliver protein drugs for the therapy of cancer and other diseases. Citation Format: Michael H. Jones, Nirk E. Quispe Calla, Callum Talbot-Cooper, Hong Zeng, Jonathan Best, Robert Smith. Low-dose crystalline cytokine macrophage mediated Trojan horse immunotherapy of solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2705.
Abstract 3784: miR-489 induces apoptosis and immunogenic cell death through targeting FOXM1 in triple negative breast cancer cells
Authors: Gourab Gupta, Ryan Titus, Yogin Patel, Shakthika Sarvanan, Hexin Chen
Journal: Cancer Research (2023)

Abstract It has been well established that microRNAs (miRNAs) have an important role in cancer sustenance and progression. Our previous studies have established the role of miR-489 as a tumor suppressor miRNA in breast cancer. However, the multiple targets of this miRNA have diversified its mechanism from preventing tumor cell proliferation to promoting cell death pathways. In this study we have aimed to establish the role of miR-489 in cell cycle inhibition, leading to Endoplasmic Reticulum stress (ER stress) and ultimately immunogenic cell death (ICD). Firstly, we found that overexpression of miR-489 in triple negative breast cancer (TNBC) cell lines including MDA-MB-231, BT 549, drastically reduced cell proliferation using colony formation assay and real-time cell analysis. Furthermore, studies like GO analysis, sequence analysis and cell cycle analysis demonstrated that miR-489 induces cell cycle arrest and apoptosis in TNBC by directly targeting FOXM1 and regulating other kinases like CDK1. It was also shown for the first time that miR-489 overexpression induces ER stress and the release of damage associated molecular patterns (DAMPs), consistent with hallmarks of ICD like Calreticulin exposure on cellular surface and ATP release, triggering phagocytosis. It was also established that miR-489-induced apoptosis lead to the elevation of cleaved caspase 3, which was responsible for the activation of PANX1 and the consequent release of ATP. In conclusion, we tried to mechanistically understand the role of miR-489 in cell cycle arrest leading to cellular stress. Stress induced apoptosis and consequent ICD was also a possible outcome and it turned out miR-489 overexpression without any other ICD inducer was good enough to trigger the release of DAMPs and elucidate an immunogenic response. Citation Format: Gourab Gupta, Ryan Titus, Yogin Patel, Shakthika Sarvanan, Hexin Chen. miR-489 induces apoptosis and immunogenic cell death through targeting FOXM1 in triple negative breast cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3784.
Abstract 4024: Overcoming ALK resistance with covalent cysteine-reactive inhibitors in lung cancer
Authors: Diane Yang, Stefan Harry, Edwin Zhang, Zavontae Oppong-Holmes, Alexander Daniel Carlin, Wenxin Yang, Abigail Smith, Maristela Onozato, Liron Bar-Peled, Anthony J. Iafrate
Journal: Cancer Research (2023)

Abstract The EML4-ALK fusion gene is the main oncogenic driver in 5% of non-small cell lung cancer and has been effectively targeted using ALK-specific tyrosine kinase inhibitors. While survival rates have improved steadily with each new generation of ALK TKI, resistance generally develops, including second site ALK kinase mutations as well as by-pass track activation. Since almost all anti-ALK approaches have focused on kinase domain inhibition, we sought to develop novel inhibitors with alternative mechanisms of action against ALK to overcome current drug resistance. Cysteine-reactive small molecule drugs may enable new mechanisms of target inhibition, and clinically successful examples of recent FDA-approved drugs in NSCLC include afatinib, osimertinib, sotorasib, and adagrasib.We aimed to explore and uncover novel cysteine-reactive covalent inhibitors of EML4-ALK. Using cysteine druggability mapping (CDM), a proteome-wide mass spectrometry target engagement assay, we first determined the landscape of reactive cysteines in ALK-positive cell lines and identified various targetable cysteines within the MAPK pathway and within the EML4-ALK fusion protein itself. To identify small molecules that modulate ALK activation, degradation, and downstream signaling, we conducted a high-content phosphorylated protein screen by testing 4,400 reactive cysteine compounds and found 20 potential hits that impacted ALK phosphorylation or expression. Using proteomic analysis, we have determined the comparative specificity of these compounds, and have ranked them based on p-ALK reduction efficiency and on their off-target binding patterns. We have initiated hit-to-lead development on a compound that binds to the EML4 portion of the fusion and we are performing a detailed analysis of its mechanism of action. To further optimize the potency of the compound, we designed, synthesized, and are testing several hundred analog compounds. By applying the hit compounds from the screen in ALK TKI-resistant models, we will be able to evaluate the ability of these compounds to overcome ALK resistance. To our knowledge, we have identified the first EML4-ALK covalent binder targeting the EML4 domain. Using the unique mechanism of action of the current ALK kinase inhibitor, we have uncovered a potential compound to overcome ALK resistance. Citation Format: Diane Yang, Stefan Harry, Edwin Zhang, Zavontae Oppong-Holmes, Alexander Daniel Carlin, Wenxin Yang, Abigail Smith, Maristela Onozato, Liron Bar-Peled, Anthony J. Iafrate. Overcoming ALK resistance with covalent cysteine-reactive inhibitors in lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4024.
Abstract 1498: Melanoma antigen gene A6 and androgen receptor interaction in bladder cancer
Authors: Prem Prakash Kushwaha, Shiv Verma, Sanjay Gupta
Journal: Cancer Research (2023)

Abstract The Melanoma Antigen Gene (MAGE) protein family is a large and highly conserved group of proteins that share a common MAGE homology domain. Interestingly, several MAGE proteins are limited in expression to reproductive tissues but are aberrantly expressed in various types of human malignancies. We have recently demonstrated overexpression of MAGE family member A6 in advance-stage bladder cancer (Cancers 13:23, 5931, 2021). However, the mechanisms involved in MAGE gene overexpression and its coregulators are currently unknown. One hypothesis is that MAGEA6 and androgen receptor (AR) signaling is involved in the etiology of bladder cancer progression. In the present study, we determined the functional relationship between MAGEA6 and AR in bladder cancer. Treatment with DHT, an AR agonist, increased AR and MAGEA6 expression in UMUC3 and J82 bladder cancer cells at the protein and transcript level. On the contrary, exposure of cells to enzalutamide, an antiandrogen, resulted in simultaneous reduction of AR and MAGEA6 more prominently in UMUC3 cells, compared to J82 harboring low MAGEA6 transcript. Dual-sgRNA CRISPR/Cas9 knockout of MAGEA6 in UMUC3 and J82 cells resulted in inhibition of cell proliferation, reduced survival, and migration potential in both cell lines. An induction of S-phase and G0/G1 phase cell cycle arrest was noted in UMUC3 and J82 cells. In silico analysis showed Arg20 and Cys557 amino acid residue of AR interacts with Asp236 and Gln106 amino acid residue of MAGEA6 through hydrogen bonds. Further confirmation of physical interaction between AR and MAGEA6, performed by immunoprecipitation of AR and probed for MAGEA6 and vice versa established interaction of AR-MAGEA6 with each other which was further confirmed by mass spectrometry analysis. In conclusion, these findings confirm the oncogenic role of MAGEA6 and its physical interaction with AR may be involved in bladder cancer progression. Citation Format: Prem Prakash Kushwaha, Shiv Verma, Sanjay Gupta. Melanoma antigen gene A6 and androgen receptor interaction in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1498.